The present invention relates to the use of phenylalkanols (gingerol analogues) in the treatment or prophylaxis of diseases by the inhibition of platelet aggregation. The present invention further relates to the use of phenylalkanols (gingerol analogues) in the treatment or prophylaxis of pain by action on sensory nerves and/or through anti-inflammatory action.
Agents directly or indirectly controlling calcium are potentially useful for the treatment of congestive heart failure, hypertension, pain, diabetes and cancer (Vincenzi, 1981) or may have cardioprotective or neuroprotective properties. Other agents of interest are those known to affect calcium channel mediated Ca2+ uptake into cells, such as the therapeutic 1,4-dihydropyridine drug nifedipine and verapamil (Triggle, 1984). They are useful antianginal drugs as well as antihypertensives. Agents that have anti-inflammatory properties and antiplatelet properties are potentially useful for the treatment of inflammation, pain, stroke and ischaemic diseases.
The gingerols are a series of natural homologues isolated from ginger, Zingiber officinale. Gingerols are classified according to their alkyl chain length eg. [6]-gingerol, [8]-gingerol (Deniff et al, 1981). A patent is published (Takeda et al, 1992) on the preparation of racemic gingerols (eg. [6]-gingerol) and their dehydrated derivatives (eg. [6]-shogaol) and their use as antipyretic and analgesic agents (no data). Another patent is published (Tanaka et al, 1987) on a shogaol derivative where the carbonyl group of the side-chain is reduced to hydroxy group and its use in the treatment of thrombosis and pain.
Agents that inhibit platelet aggregation may be used for the treatment of cardiovascular diseases and stroke. Platelets play an essential role in blood clotting at sites of wound injury, but unwanted activation of platelets in the circulation can give rise to thrombus formation, and is implicated in the onset of stroke, myocardial infarction, and other diseases. Therapeutic modalities aimed at secondary prevention of stroke and ischaemic diseases include vascular surgery, anticoagulant and platelet aggregation inhibition. Among these, the platelet aggregation inhibition appears to be the most promising because in fast-flowing vessels thrombi are composed mainly of platelets with little fibrin. Recent clinical trials have indicated that antiplatelet therapy protects a wide range of patients at high risk of occlusive vascular disease (Antiplatelet Trialists"" Collaboration, 1994). Medium dose aspirin is the most widely used antiplatelet regimen, and no other regimen appeared significantly more effective at preventing myocardial infarction and stroke. However, gastrointestinal tract upset, particularly peptic ulcer, is a common problem associated with the use of aspirin (Roderick, 1993). In addition, complications in some disease conditions such as diabetes and asthma are of major concern in the use of aspirin. A new safe antiplatelet therapy is therefore required.
There is a need for safe and effective agents for the treatment of pain and inflammation, particularly arthritis. The use of analgesics such as non-steroidal anti-inflammatory agents (NSAIDS), paracetamol and morphine still remain a primary therapy for such conditions. Each of these agents, however, has limitations. Aspirin and newer non-steroidal anti-inflammatory agents can cause gastrointestinal discomfort and eventually the development of peptic ulcer. Paracetamol may produce liver and kidney toxicity with chronic use. Morphine, though effective, can be addictive and exhibit tolerance. Recently, a topical analgesic has been developed from capsaicin for control of pain (anti-nociception). Capsaicin has also been used extensively for research in neurosciences, where it has benefit in the modulation of sensory nerve activity (nerves which transmit sensations of pain-causing stimuli from the periphery to the brain). Capsaicin has also yielded important knowledge about pain pathways. However, capsaicin is an irritant and cannot be administered systemically because of its potential to cause neuro-inflammation. Its use as a topical agent is also limited for several reasons: it causes mild to moderate burning sensation, erythema and stinging after application; severe irritation to sensitive organs such as eyes; it cannot be used on broken or irritated skin; excessive inhalation of aerosolised dried cream may cause coughing, which is the most commonly reported systemic side-effect associated with the use of capsaicin preparations. Higher doses may produce neurotoxic effects through mechanisms not completely understood. Development of more effective anti-nociceptive agents is imperative.
Stroke and ischaemic diseases that afflict millions of people world-wide, are among the most common maladies affecting people in industrialised countries. Current efforts directed at reducing the morbidity and mortality of these disease conditions are aimed at both relief and preventative therapies. The platelet aggregation inhibition appears to be the most promising modality aimed at prevention of stroke and ischaemic diseases because in fast-flowing vessels thrombi are composed mainly of platelets with little fibrin.
There is great need to develop more effective drugs with novel action. Substances that are the subject of the present invention are typically substances that exert useful medicinal actions through mechanisms where calcium is either directly or indirectly involved. For example, hypertension including stroke are common disorders with extremely high mortality rate. Their incidence is steadily increasing despite a substantial haemostasis improvement by a number of therapeutic regiments (Salmo, 1995).